tbuckley/cabot-search huggingface dataset:
Evolution of antigen-specific follicular helper T cell transcription from effector function to memory
Authors: Amanda M. Robinson, Brett W. Higgins, Andrew G. Shuparski, Karen B. Miller, Louise J. McHeyzer-Williams, Michael G. McHeyzer-Williams
Journal: Science Immunology (2022)

Understanding how follicular helper T cells (TFH) regulate the specialization, maturation, and differentiation of adaptive B cell immunity is crucial for developing durable high-affinity immune protection. Using indexed single-cell molecular strategies, we reveal a skewed intraclonal assortment of higher-affinity T cell receptors and the distinct molecular programming of the localized TFH compartment compared with emigrant conventional effector T H cells. We find a temporal shift in B cell receptor class switch, which permits identification of inflammatory and anti-inflammatory modules of transcriptional programming that subspecialize TFH function before and during the germinal center (GC) reaction. Late collapse of this local primary GC reaction reveals a persistent post-GC TFH population that discloses a putative memory TFH program. These studies define subspecialized antigen-specific TFH transcriptional programs that progressively change with antibody class-specific evolution of high-affinity B cell immunity and a memory TFH transcriptional program that emerges upon local GC resolution.
Epithelial-to-Mesenchymal Transition Supports Ovarian Carcinosarcoma Tumorigenesis and Confers Sensitivity to Microtubule Targeting with Eribulin
Authors: Gwo Yaw Ho, Elizabeth L. Kyran, Justin Bedo, Matthew J. Wakefield, Darren P. Ennis, Hasan B. Mirza, Cassandra J. Vandenberg, Elizabeth Lieschke, Andrew Farrell, Anthony Hadla, Ratana Lim, Genevieve Dall, James E. Vince, Ngee Kiat Chua, Olga Kondrashova, Rosanna Upstill-Goddard, Ulla-Maja Bailey, Suzanne Dowson, Patricia Roxburgh, Rosalind M. Glasspool, Gareth Bryson, Andrew V. Biankin, Susanna L. Cooke, Gayanie Ratnayake, Orla McNally, Nadia Traficante, Anna DeFazio, S. John Weroha, David D. Bowtell, Iain A. McNeish, Anthony T. Papenfuss, Clare L. Scott, Holly E. Barker
Journal: Cancer Research (2022)

Ovarian carcinosarcoma (OCS) is an aggressive and rare tumor type with limited treatment options. OCS is hypothesized to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analyzed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated that the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumors. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts. Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a downregulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate that EMT plays a key role in OCS tumorigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes.Genomic analyses and preclinical models of ovarian carcinosarcoma support the conversion theory for disease development and indicate that microtubule inhibitors could be used to suppress EMT and stimulate antitumor immunity.
BATF epigenetically and transcriptionally controls the activation program of regulatory T cells in human tumors
Authors: Kota Itahashi, Takuma Irie, Junichiro Yuda, Shogo Kumagai, Tokiyoshi Tanegashima, Yi-Tzu Lin, Sho Watanabe, Yasushi Goto, Jun Suzuki, Keiju Aokage, Masahiro Tsuboi, Yosuke Minami, Genichiro Ishii, Yuichiro Ohe, Wataru Ise, Tomohiro Kurosaki, Yutaka Suzuki, Shohei Koyama, Hiroyoshi Nishikawa
Journal: Science Immunology (2022)

Regulatory T (T reg ) cells suppress effective antitumor immunity in tumor-bearing hosts, thereby becoming promising targets in cancer immunotherapy. Despite the importance of T reg cells in tumor immunity, little is known about their differentiation process and epigenetic profiles in the tumor microenvironment (TME). Here, we showed that T reg cells in the TME of human lung cancers harbored a completely different open chromatin profile compared with CD8 + T cells, conventional CD4 + T cells in the TME, and peripheral T reg cells. The integrative sequencing analyses including ATAC, single-cell RNA, and single-cell ATAC sequencing revealed that BATF, IRF4, NF-κB, and NR4A were important transcription factors for T reg cell differentiation in the TME. In particular, BATF was identified as a key regulator, which leveraged T reg cell differentiation through epigenetically controlling activation-associated gene expression, resulting in the robustness of T reg cells in the TME. The single-cell sequencing approaches also revealed that tissue-resident and tumor-infiltrating T reg cells followed a common pathway for differentiation and activation in a BATF-dependent manner heading toward T reg cells with the most differentiated and activated phenotypes in tissues and tumors. BATF deficiency in T reg cells remarkably inhibited tumor growth, and high BATF expression was associated with poor prognosis in lung cancer, kidney cancer, and melanoma. These findings indicate one of the specific chromatin remodeling and differentiation programs of T reg cells in the TME, which can be applied in the development of T reg cell–targeted therapies.
When I use a word . . . . Too much healthcare—incompetence and hierarchiology
Authors: Jeffrey K Aronson
Journal: BMJ (2022)

The Peter principle, named after Laurence J Peter, who first enunciated it, describes a common problem inherent in the ways in which individuals perform their allotted tasks within a hierarchical system: “In a hierarchy every employee tends to rise to his level of incompetence.” The problem is unavoidable. Pseudopromotions, such as kicking an employee upstairs or sideways are ineffective, as are several other strategies. In medical practice, working in teams may help to mitigate the effects, when competent juniors protect their incompetent bosses, but not when an individual works alone. The best strategy is prevention, by considering, through benefit:harm balance analysis, why one should not seek or accept promotion. However, once incompetence sets in, the affected individual loses the ability to understand the problem.
<i>Helicobacter pylori</i> employs a general protein glycosylation system for the modification of outer membrane adhesins
Authors: Kai-Wen Teng, Kai-Siang Hsieh, Ji-Shiuan Hung, Chun-Jen Wang, En-Chi Liao, Pei-Chun Chen, Ying-Hsuan Lin, Deng-Chyang Wu, Chun-Hung Lin, Wen-Ching Wang, Hong-Lin Chan, Shau-Ku Huang, Mou-Chieh Kao
Journal: Gut Microbes (2022)

Helicobacter pylori infection is associated with the development of several gastric diseases including gastric cancer. To reach a long-term colonization in the host stomach, H. pylori employs multiple outer membrane adhesins for binding to the gastric mucosa. However, due to the redundancy of adhesins that complement the adhesive function of bacteria, targeting each individual adhesin alone usually achieves nonideal outcomes for preventing bacterial adhesion. Here, we report that key adhesins AlpA/B and BabA/B in H. pylori are modified by glycans and display a two-step molecular weight upshift pattern from the cytoplasm to the inner membrane and from the inner membrane to the outer membrane. Nevertheless, this upshift pattern is missing when the expression of some enzymes related to lipopolysaccharide (LPS) biosynthesis, including the LPS O-antigen assembly and ligation enzymes WecA, Wzk, and WaaL, is disrupted, indicating that the underlying mechanisms and the involved enzymes for the adhesin glycosylation are partially shared with the LPS biosynthesis. Loss of the adhesin glycosylation not only reduces the protease resistance and the stability of the tested adhesins but also changes the adhesin-binding ability. In addition, mutations in the LPS biosynthesis cause a significant reduction in bacterial adhesion in the in vitro cell-line model. The current findings reveal that H. pylori employs a general protein glycosylation system related to LPS biosynthesis for adhesin modification and its biological significance. The enzymes required for adhesin glycosylation rather than the adhesins themselves are potentially better drug targets for preventing or treating H. pylori infection.
Antigen-specific depletion of CD4 <sup>+</sup> T cells by CAR T cells reveals distinct roles of higher- and lower-affinity TCRs during autoimmunity
Authors: Jaeu Yi, Aidan T. Miller, Angela S. Archambault, Andrew J. Jones, Tara R. Bradstreet, Sravanthi Bandla, Yu-Sung Hsu, Brian T. Edelson, You W. Zhou, Daved H. Fremont, Takeshi Egawa, Nathan Singh, Gregory F. Wu, Chyi-Song Hsieh
Journal: Science Immunology (2022)

Both higher- and lower-affinity self-reactive CD4+ T cells are expanded in autoimmunity; however, their individual contribution to disease remains unclear. We addressed this question using peptide-MHCII chimeric antigen receptor (pMHCII-CAR) T cells to specifically deplete peptide-reactive T cells in mice. Integration of improvements in CAR engineering with TCR repertoire analysis was critical for interrogating in vivo the role of TCR affinity in autoimmunity. Our original MOG35-55 pMHCII-CAR, which targeted only higher-affinity TCRs, could prevent the induction of experimental autoimmune encephalomyelitis (EAE). However, pMHCII-CAR enhancements to pMHCII stability, as well as increased survivability via overexpression of a dominant-negative Fas, were required to target lower-affinity MOG-specific T cells and reverse ongoing clinical EAE. Thus, these data suggest a model in which higher-affinity autoreactive T cells are required to provide the "activation energy" for initiating neuroinflammatory injury, but lower-affinity cells are sufficient to maintain ongoing disease.
A biodegradable magnesium surgical staple for colonic anastomosis: In vitro and in vivo evaluation
Authors: Yue Zhang, Jian Cao, Mengmeng Lu, Yi Shao, Kewei Jiang, Xiaodong Yang, Xiaoyu Xiong, Shan Wang, Chenglin Chu, Feng Xue, Yingjiang Ye, Jing Bai
Journal: Bioactive Materials (2022)

Staplers have been widely used in the clinical treatment of gastrointestinal reconstruction. However, the current titanium (Ti) staple will remain in the human body permanently, resulting in some adverse effects. In this study, we developed a type of biodegradable staple for colonic anastomosis using 0.3 mm diameter magnesium (Mg) alloy wires. The wire surface was modified by micro-arc oxidation treatment (MAO) and then coated with poly-l-lactic acid (PLLA) to achieve a moderate degradation rate matching the tissue healing process. The results of tensile tests on isolated porcine colon tissue anastomosed by Mg and Ti staples showed that the anastomotic property of Mg staples was almost equal to that of Ti staples. The in vitro degradation tests indicated the dual-layer coating effectively enhanced the corrosion resistance and maintained the tensile force of the coated staple stable after 14-day immersion in the simulated colonic fluid (SCF). Furthermore, 24 beagle dogs were employed to conduct a comparison experiment using Mg-based and clinical Ti staples for 90-day implantation by ent-to-side anastomosis of the colon. The integrated structure of Mg-based staples was observed after 7 days and completely degraded after 90 days. All animals did not have anastomotic leakage and stenosis, and 12 dogs with Mg-based staples fully recovered after 90 days without differences in visceral ion levels and other side effects. The favorable performance makes this Mg-based anastomotic staple an ideal candidate for colon reconstruction.
Transient visual loss following CT-guided percutaneous core needle biopsy of a lung lesion
Authors: Karina Bennett, Karla Totton, Arianna Misacas, Fiona Caswell, David Miller
Journal: Thorax (2022)

All 151 patients of 75 years and over in one practice were visited at home to survey their health and how they managed their medicines. Altogehter 87% were on regular treatment, 34% taking three or four different drugs each day. Most were responsible for their own drugs and managed them well, but many left their drugs in exposed places and were uncertain about how to dispose of unwanted medicines. Overall they were prescribed about three times the number of drugs prescribed for the general population, and women took twice as many drugs regularly as men. Although many drugs were obtained directly from a pharmacist, his advice was rarely sought. Most were labelled, but more explicit instructions about indications for taking the drug would have been helpful, and information about hoarded drugs would have been enhanced by dispensing and expiry dates. Treatment was facilitated when patients brought their drugs to the consultation and careful records were made of repeat prescriptions. As so many patients take three or more different types of drugs each day a container in which a day9s supply could be laid out would be useful.
Dynamic changes in host immune system and gut microbiota are associated with the production of SARS-CoV-2 antibodies
Authors: Maozhen Han, Yixuan Huang, Hongya Gui, Yixuan Xiao, Maozhang He, Jiling Liu, Xiujing Cao, Meijuan Zheng, Min Lu, Weihua Jia, Hui Li, Xiaoyan Wang, Na Zhang, Shu-an Kong, Xiaohui Liu, Yonggui Wu, Fengchang Wu, Shenghai Huang
Journal: Gut (2022)
Nomenclature of HBV core protein-targeting antivirals
Authors: Fabien Zoulim, Adam Zlotnick, Stephanie Buchholz, Eric Donaldson, John Fry, Anuj Gaggar, Jianming Hu, Michael Kann, Oliver Lenz, Kai Lin, Nagraj Mani, Michael Nassal, William Delaney, Su Wang, Gabriel Westman, Veronica Miller, Harry L A Janssen
Journal: Nature Reviews Gastroenterology & Hepatology (2022)
PRL2 phosphatase enhances oncogenic FLT3 signaling via dephosphorylation of the E3 ubiquitin ligase CBL at tyrosine 371
Authors: Hongxia Chen, Yunpeng Bai, Michihiro Kobayashi, Shiyu Xiao, Wenjie Cai, Sergio Barajas, Sisi Chen, Jinmin Miao, Frederick Nguele Meke, Sasidhar Vemula, James P. Ropa, James M. Croop, H. Scott Boswell, Jun Wan, Yuzhi Jia, Huiping Liu, Loretta S. Li, Jessica K. Altman, Elizabeth A. Eklund, Peng Ji, Wei Tong, Hamid Band, Danny T. Huang, Leonidas C. Platanias, Zhong-Yin Zhang, Yan Liu
Journal: Blood (2022)
mTOR inhibition attenuates cTfh cell dysregulation and chronic T-cell activation in multilineage immune cytopenias
Authors: Deepak Kumar, Thinh H. Nguyen, Carolyn M. Bennett, Chengyu Prince, Laura Lucas, Sunita Park, Taylor Lawrence, Karin Chappelle, Mariam Ishaq, Edmund K. Waller, Sampath Prahalad, Michael Briones, Shanmuganathan Chandrakasan
Journal: Blood (2022)
Progression-Free Survival and Patterns of Response in Patients With Relapsed High-Risk Neuroblastoma Treated With Irinotecan/Temozolomide/Dinutuximab/Granulocyte-Macrophage Colony-Stimulating Factor
Authors: Benjamin J. Lerman, Yimei Li, Cecilia Carlowicz, Meaghan Granger, Thomas Cash, Arhanti Sadanand, Katherine Somers, Aeesha Ranavaya, Brian D. Weiss, Michelle Choe, Jennifer H. Foster, Navin Pinto, Daniel A. Morgenstern, Margarida Simão Rafael, Keri A. Streby, Rachel N. Zeno, Rajen Mody, Sahr Yazdani, Ami V. Desai, Margaret E. Macy, Suzanne Shusterman, Sara M. Federico, Rochelle Bagatell
Journal: Journal of Clinical Oncology (2022)

Although chemoimmunotherapy is widely used for treatment of children with relapsed high-risk neuroblastoma (HRNB), little is known about timing, duration, and evolution of response after irinotecan/temozolomide/dinutuximab/granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) therapy.Patients eligible for this retrospective study were age < 30 years at diagnosis of HRNB and received ≥ 1 cycle of I/T/DIN/GM-CSF for relapsed or progressive disease. Patients with primary refractory disease who progressed through induction were excluded. Responses were evaluated using the International Neuroblastoma Response Criteria.One hundred forty-six patients were included. Tumors were MYCN-amplified in 50 of 134 (37%). Seventy-one patients (49%) had an objective response to I/T/DIN/GM-CSF (objective response; 29% complete response, 14% partial response [PR], 5% minor response [MR], 21% stable disease [SD], and 30% progressive disease). Of patients with SD or better at first post-I/T/DIN/GM-CSF disease evaluation, 22% had an improved response per International Neuroblastoma Response Criteria on subsequent evaluation (13% of patients with initial SD, 33% with MR, and 41% with PR). Patients received a median of 4.5 (range, 1-31) cycles. The median progression-free survival (PFS) was 13.1 months, and the 1-year PFS and 2-year PFS were 50% and 28%, respectively. The median duration of response was 15.9 months; the median PFS off all anticancer therapy was 10.4 months after discontinuation of I/T/DIN/GM-CSF.Approximately half of patients receiving I/T/DIN/GM-CSF for relapsed HRNB had objective responses. Patients with initial SD were unlikely to have an objective response, but > 1 of 3 patients with MR/PR on first evaluation ultimately had complete response. I/T/DIN/GM-CSF was associated with extended PFS in responders both during and after discontinuation of treatment. This study establishes a new comparator for response and survival in patients with relapsed HRNB.
Multiple COVID-19 vaccine doses in CLL and MBL improve immune responses with progressive and high seroconversion
Authors: Yandong Shen, Jane A. Freeman, Juliette Holland, Kartik Naidu, Ann Solterbeck, Nenna Van Bilsen, Paul Downe, Ian Kerridge, Lucinda Wallman, Anouschka Akerman, Anupriya Aggarwal, Vanessa Milogiannakis, Gabriela Martins Costa Gomes, Chloe M. Doyle, Kerrie J. Sandgren, Stuart Turville, Anthony L. Cunningham, Stephen P. Mulligan
Journal: Blood (2022)
PD-1/CTLA-4 Blockade Leads to Expansion of CD8+PD-1int TILs and Results in Tumor Remission in Experimental Liver Cancer
Authors: Sandra Bufe, Artur Zimmermann, Sarina Ravens, Immo Prinz, Laura Elisa Buitrago-Molina, Robert Geffers, Norman Woller, Florian Kühnel, Steven R. Talbot, Fatih Noyan, Michael Peter Manns, Heiner Wedemeyer, Matthias Hardtke-Wolenski, Elmar Jaeckel, Ana C. Davalos-Misslitz
Journal: Liver Cancer (2022)

Background: Checkpoint inhibitors act on exhausted CD8+ T cells and restore their effector function in chronic infections and cancer. The underlying mechanisms of action appear to differ between different types of cancer and are not yet fully understood. Methods: Here, we established a new orthotopic HCC model to study the effects of checkpoint blockade on exhausted CD8+ tumor-infiltrating lymphocytes (TILs). The tumors expressed endogenous levels of HA, which allowed the study of tumor-specific T cells. Results: The induced tumors developed an immune-resistant TME in which few T cells were found. The few recovered CD8+ TILs were mostly terminally exhausted and expressed high levels of PD-1. PD-1/CTLA-4 blockade resulted in a strong increase in the number of CD8+ TILs expressing intermediate amounts of PD-1, also called progenitor-exhausted CD8+ TILs, while terminally exhausted CD8+ TILs were almost absent in the tumors of treated mice. Although transferred naïve tumor-specific T cells did not expand in the tumors of untreated mice, they expanded strongly after treatment and generated progenitor-exhausted but not terminally exhausted CD8+ TILs. Unexpectedly, progenitor-exhausted CD8+ TILs mediated the antitumor response after treatment with minimal changes in their transcriptional profile. Conclusion: In our model, few doses of checkpoint inhibitors during the priming of transferred CD8+ tumor-specific T cells were sufficient to induce tumor remission. Therefore, PD-1/CTLA-4 blockade has an ameliorative effect on the expansion of recently primed CD8+ T cells while preventing their development into terminally exhausted CD8+ TILs in the TME. This finding could have important implications for future T-cell therapies.
Regorafenib versus Cabozantinib as a Second-Line Treatment for Advanced Hepatocellular Carcinoma: An Anchored Matching-Adjusted Indirect Comparison of Efficacy and Safety
Authors: Philippe Merle, Masatoshi Kudo, Stanimira Krotneva, Kirhan Ozgurdal, Yun Su, Irina Proskorovsky
Journal: Liver Cancer (2022)

The tyrosine kinase inhibitors regorafenib and cabozantinib remain the mainstay in second-line treatment of advanced hepatocellular carcinoma (HCC). There is currently no clear evidence of superiority in efficacy or safety to guide choice between the two treatments.We conducted an anchored matching-adjusted indirect comparison using individual patient data from the RESORCE trial of regorafenib and published aggregate data from the CELESTIAL trial of cabozantinib. Second-line HCC patients with prior sorafenib exposure of ≥3 months were included in the analyses. Hazard ratios (HRs) and restricted mean survival time (RMST) were estimated to quantify differences in overall survival (OS) and progression-free survival (PFS). Safety outcomes compared were rates of grade 3 or 4 adverse events (AEs), occurring in >10% of patients, and discontinuation or dose reduction due to treatment-related AEs.After matching adjustment for differences in baseline patient characteristics, regorafenib showed a favorable OS (HR, 0.80; 95% CI: 0.54, 1.20) and ∼3-month-longer RMST over cabozantinib (RMST difference, 2.76 months; 95% CI: -1.03, 6.54), although not statistically significant. For PFS, there was no numerical difference in HR (HR, 1.00; 95% CI: 0.68, 1.49) and no clinically meaningful difference based on RMST analyses (RMST difference, -0.59 months; 95% CI: -1.83, 0.65). Regorafenib showed a significantly lower incidence of discontinuation (risk difference, -9.2%; 95% CI: -17.7%, -0.6%) and dose reductions (-15.2%; 95% CI: -29.0%, -1.5%) due to treatment-related AEs (any grade). Regorafenib was also associated with a lower incidence (not statistically significant) of grade 3 or 4 diarrhea (risk difference, -7.1%; 95% CI: -14.7%, 0.4%) and fatigue (-6.3%; 95% CI: -14.6%, 2.0%).This indirect treatment comparison suggests, relative to cabozantinib, that regorafenib could be associated with favorable OS (not statistically significant), lower rates of dose reductions and discontinuation due to treatment-related AEs, and lower rates of severe diarrhea and fatigue.
Epidemiological and clinical characteristics of patients with monkeypox in the GeoSentinel Network: a cross-sectional study
Authors: Kristina M Angelo, Teresa Smith, Daniel Camprubí-Ferrer, Leire Balerdi-Sarasola, Marta Díaz Menéndez, Guillermo Servera-Negre, Sapha Barkati, Alexandre Duvignaud, Kristina L B Huber, Arpita Chakravarti, Emmanuel Bottieau, Christina Greenaway, Martin P Grobusch, Diogo Mendes Pedro, Hilmir Asgeirsson, Corneliu Petru Popescu, Charlotte Martin, Carmelo Licitra, Albie de Frey, Eli Schwartz, Michael Beadsworth, Susana Lloveras, Carsten S Larsen, Sarah Anne J Guagliardo, Florence Whitehill, Ralph Huits, Davidson H Hamer, Phyllis Kozarsky, Michael Libman, Lucille Blumberg, Hélène Chaussade, Arnaud Desclaux, Eric Florence, Simin Aysel Florescu, Hedvig Glans, Marielle Glynn, Abraham Goorhuis, Marina Klein, Denis Malvy, Andrea McCollum, José Muñoz, Duc Nguyen, Laura Quilter, Camilla Rothe, Patrick Soentjens, Camille Tumiotto, Jef Vanhamel
Journal: The Lancet Infectious Diseases (2022)